Patients with localized renal cell cancer (RCC) are often cured following surgical resection. However, a significant proportion of patients will experience recurrence or present with metastatic disease at distant sites and may be deemed incurable. The worldwide incidence of RCC is rising, affecting more than 271,000 people and resulting in 116,000 deaths each year. Unfortunately, advanced RCC is typically resistant to classical chemotherapy and radiotherapy. Previously, non-specific immunotherapies such as interleukin-2 and interferon were used in hopes of improving cancer immunity, leading to rare but durable responses. However, enthusiasm for these immunotherapies has waned due to limited patient responses, their excessive toxicities, and the emergence of alternative targeted therapies that have resulted in improved clinical endpoints for patients with metastatic RCC (mRCC). Strides in targeted treatment can be attributed to an improved understanding of the molecular underpinnings that cause and drive the progression of renal cell cancers. More recently, interest in immunotherapies has resurfaced, as agents inhibiting specific checkpoints involved in cancer immune evasion have demonstrated promising activity in patients with mRCC. Here we review the novel targeted agents, biomarkers and immunotherapies that promise to change the clinical outcomes for patients with advanced RCC.